US 8,575,301 B2 · Assignee: Ethicon, Inc. · Inventors: Andjelic; Sasa et al.
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A co-polyester which includes the reaction product of a polycondensation polyester and epsilon-caprolactone, wherein the polycondensation polyester comprises the reaction product of diglycolic acid and/or a derivative thereof and a diol. The co-polyester is injectable and absorbable into animal, such as human, tissue and can be used for facial cosmetic or reconstructive surgery of soft tissue. Another embodiment is directed to a method for preventing adhesion using a co-polyester comprising the reaction product of a polycondensation polyester and epsilon-caprolactone, wherein the polycondensation polyester comprises the reaction product of diglycolic acid and/or a derivative thereof and a diol, and the co-polyester comprises about 40 to 50% by weight of the polycondensation polyester based on the total weight of the co-polyester.
The repair or augmentation of soft tissue, such as soft tissue defects, or contour abnormalities caused by a variety of factors, such as facial defects, acne, surgical scarring or aging, accidents or purely for cosmetic reasons, has proven to be challenging. A number of materials have been used to correct soft tissue defects or augment soft tissue, with varying degrees of success. In the past, liquid silicone was used to correct minor soft tissue defects where minimal mechanical stress was present at the recipient's site. Unfortunately, it appears that liquid silicone from these injections may migrate to distant body parts and cause a variety of physiological and clinical problems. In response to these problems and the misuse of liquid silicone, the FDA at times prohibited the use of liquid silicone in humans. In the 1970's, reconstituted injectable bovine collagen became available and a
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The invention relates to injectable, absorbable polymer formulations for plastic and reconstructive surgery applications, and methods of using thereof with an absorbable co-polyester of a condensation polyester and epsilon-caprolactone. The invention also relates to a method of preventing adhesions using absorbable co-polyester of a polycondensation polyester and at least one lactone.
The repair or augmentation of soft tissue, such as soft tissue defects, or contour abnormalities caused by a variety of factors, such as facial defects, acne, surgical scarring or aging, accidents or purely for cosmetic reasons, has proven to be challenging. A number of materials have been used to correct soft tissue defects or augment soft tissue, with varying degrees of success. In the past, liquid silicone was used to correct minor soft tissue defects where minimal mechanical stress was present at the recipient's site. Unfortunately, it appears that liquid silicone from these injections may migrate to distant body parts and cause a variety of physiological and clinical problems. In response to these problems and the misuse of liquid silicone, the FDA at times prohibited the use of liquid silicone in humans.
In the 1970's, reconstituted injectable bovine collagen became available and appeared to be an effective treatment for soft tissue defects. However, over time, the benefits of the collagen treatment have proven to be short-lived; the collagen reabsorbs in two to three months. Additionally, safety measures must be employed with this material to avoid allergic reactions to the bovine proteins in the collagen. To solve these shortcomings, crosslinked collagen has been introduced to extend the effect of treatments to approximately six
months. However, allergic reactions may still occur with the cross-linked collagen material and frequent re-administration of the cross-linked material is still required.
U.S. Pat. No. 6,716,251, assigned to Aventis Pharmaceuticals Holdings, Inc., describes the use of an injection implant for filling up wrinkles, thin lines, skin cracks and scars, for reparative or plastic surgery, aesthetic dermatology, and for filling up gums in dental treatment. The implant includes biologically absorbable polymer microspheres or microparticles suspended in a gel. Two polymer families are described as being suitable, the polycaprolactones (and in particular the poly-epsilon-caprolactones), as well as the polylactides (polylactic acids or PLA), the poly-glycolides (polyglycolic acids or PGA) and their copolymers (polylactic-co-glycolic acids or PLAGA).
U.S. Pat. No. 4,938,763, assigned to Atrix Laboratories, Inc., discloses the use of biodegradable polymers as prosthetic implants and controlled-release, drug-delivery systems which can be administered as liquids via, for example, a syringe and needle, but which coagulate or cure shortly after dosing to form a solid. The implants are biodegradable because they are made from biodegradable polymers and copolymers comprising two types of polymer systems: thermoplastic and thermosetting. Examples of thermoplastic systems are polylactides, polyglycolides, polycaprolactones, and polyamides, preferably polylactides, polycaprolactones, and copolymers thereof with glycolide in which there are more amorphous regions to enhance solubility. The polymers used in the thermosetting system are multifunctional polymers which are first synthesized via copolymerization of either DL-lactide or L-lactide with epsilon-caprolactone. The polyol-terminated prepolymers are then converted to acrylic ester-terminated prepolymers, preferably by acylation of the alcohol terminus with acryloyl chloride via a Sohotten-Baumann-like technique, i.e., reaction of acyl halides with alcohols. The acrylic ester-terminated prepolymers may also be synthesized in other ways, such as reaction of carboxylic acids (i.e., acrylic or methacrylic acid) with alcohols, reaction of carboxylic acid esters (i.e., methyl acrylate or methyl methacrylate) with alcohols by transesterification, and reaction of isocyanatoalkyl acrylates (i.e. isocyanatoethyl methacrylate) with alcohols.
Adhesion formation after peritoneal surgery is a major cause of postoperative bowel obstruction, in fertility, and chronic pelvic pain. In addition, adhesion formation can occur after abdominal, gynecological, cardiac, thoracic, spinal, ENT, or orthopedic (e.g. tendon, joint, and knee) surgery. Therefore, a methodology by which adhesion formulation after surgery could be reduced or prevented would be of great benefit in reducing postoperative morbidity.
The most straightforward approach to reducing the incidence of adhesion formation remains physically maintaining the adhesiogenic surfaces apart with a mechanical barrier. For example, U.S. Pat. No. 6,403,655, assigned to Ethicon, Inc., describes a method of preventing adhesion formation between tissues by placing a polyoxaester adhesion prevention barrier between such tissues. Exemplified in the disclosure are a polyoxaester of 3,6-dioxaoctanedioic acid and ethylene glycol, as well as a copolymer of polyoxaester/caprolactone/glycolide.
U.S. Pat. No. 5,644,002 assigned to Ethicon, Inc., describes absorbable polymers and blends of polycondensation polyester and aliphatic polyesters based on lactone monomers, where the polycondensation polyester is the reaction product of diglycolic acid and an alcohol selected from the group consisting of glycerol, pentaerythitol, trimethylolpropane, hydroxyl terminated polyethylene glycols, ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butylene glycol, dipropylene glycol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, and 1,8-octanediol. This reference teaches that the incorporation of hydroxyl terminated poly(ethylene glycol)s in the polycondensation polyester is desirable because it leads to polymers which are useful as adhesion prevention barriers. Additionally, this reference discloses that ultrathin coatings of about 1 to about 1000 microns can be applied to tissue surfaces for the prevention of adhesions. Some compositions of this reference may be used as soft tissue augmentation fillers.
U.S. Pat. Nos. 3,997,512, 4,048,256, 4,076,798, 4,095,600, 4,118,470, and 4,122,129 assigned to American Cyanamid Company, describe biocompatible and absorbable polycondensation polyesters, which are the polycondensation product of diglycolic acid and glycols such as ethylene glycol, diethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, and the like. Specifically, U.S. Pat. No. 4,095,600 describes a reaction product of (a) about 2 to 50% by weight of the polycondensation polyester and (b) polyglycolic acid, based on the total weight of the polycondensation polyester and polyglycolic acid, to form a self-supporting polymeric film for use, for example, in drug delivery. This reference is silent with respect to use of the composition for adhesion prevention.
In one aspect, the invention is directed to a co-polyester suitable for plastic and reconstructive surgery. The co-polyester includes the reaction product of a polycondensation polyester and epsilon-caprolactone, wherein the polycondensation polyester comprises the reaction product of diglycolic acid and/or a derivative thereof and a diol.
The co-polyester may comprise about 50 to about 80% by weight of the epsilon-caprolactone. The co-polyester may have Tg of about -30 to about -60.degree. C. and weight average molecular weight of about 10,000 to about 30,000 g/mol.
Alternatively, the co-polyester may comprise about 60 to about 80% by weight of the epsilon-caprolactone, have Tg of about -50 to about -60.degree. C. and weight average molecular weight of about 3,000 to about 10,000 g/mol.
An embodiment is directed to a process for preparing a co-polyester comprising reacting diglycolic acid and/or a derivative thereof with a diol to produce a dihydroxy poly (alkylene diglycolate) and/or a dihydroxy poly (diol diglycolate). Subsequently, a dihydroxy poly (alkylene diglycolate) and/or a dihydroxy poly (diol diglycolate) homopolymer is reacted with epsilon-caprolactone to produce the co-polyester which includes about 50 to about 80% by weight of the epsilon-caprolactone, based on the total weight of the co-polyester.
Another embodiment is directed to a process for preparing a co-polyester having weight average molecular weight of about 3,000 to about 10,000, comprising reacting diglycolic acid and/or a derivative thereof with ethylene glycol to produce poly(ethylene diglycolate) (PEDG), or with diethylene glycol to produce poly(ethoxyethylene diglycolate) (PEEDG), either one having weight average molecular weight of from about 1,000 to about 2,000 g/mol, and subsequently reacting the PEDG or PEEDG with an alcohol and epsilon-caprolactone to produce the co-polyester.
There is also provided a method of filling soft tissue comprising administering to the soft tissue a co-polyester which includes the reaction product of a polycondensation polyester and epsilon-caprolactone, wherein the polycondensation polyester comprises the reaction product of diglycolic acid and/or a derivative thereof and a diol. The co-polyester may have Tg of about
-30 to about -60.degree. C. and weight average molecular weight of about 10,000 to about 30,000 g/mol. Alternatively, the co-polyester may have Tg of about -50 to about -60.degree. C. and weight average molecular weight of about 3,000 to about 10,000 g/mol.
In another aspect, the invention is directed to a method for preventing adhesion using a co-polyester of a different embodiment, which comprises the reaction product of a polycondensation polyester and at least one lactone, wherein the polycondensation polyester comprises the reaction product of diglycolic acid and/or a derivative thereof and ethylene glycol; and the co-polyester comprises about 40 to 50% by weight of the polycondensation polyester based on the total weight of the co-polyester.
FIG. 1 presents a correlation between hydrolysis profiler and in vivo data for the absorbable polymers of Example 3.
1. Co-Polyesters and Use Thereof for Plastic and Reconstructive Surgery
In this application a discussion of a singular component, composition or ingredient includes the discussion of plurality thereof and vice versa. For example, discussion (or disclosure) of a co-polyester also includes disclosure of co-polyesters.
Unless indicated otherwise, inherent viscosity (IV) measurements included in the application are obtained by conducting the measurements in a 0.1 g/dL solution of hexafluoroisopropanol (HFIP) at 25.degree. C.
The co-polyester of this embodiment and composition(s) including such co-polyester are relatively long lasting absorbable synthetic fillers that minimize or eliminate frequent body injections. The co-polyester and composition(s) are liquid at ambient conditions and/or at the temperature of a human body. In addition, the co-polyester of this embodiment comprises a hydrophilic poly(ethylene diglycolate) component (or similar hydrophilic components) that, when injected into aqueous media, allows partial swelling of the co-polyester implant making the material very soft, fully compressible but yet such that it maintains its shape during long residual time. The polymers (i.e., co-polyesters) of this embodiment are liquids or soft solids with the inherent viscosities (IV) ranging between about 0.25 to about 0.90 dL/g. This viscosity range is high enough to minimize tissue reactions that are often associated with low molecular weight polymers. A composition comprising the co-polyester and a certain amount of a biocompatible solvent, such as benzyl benzoate or tetraglycol, allows for less painful polymer injections with minimal tissue reactions. In an alternative type of a co-polyester included in this embodiment (discussed below), the co-polyester has inherent viscosities (IV) ranging between about 0.10 to about 0.30 dL/g.
The co-polyester of this embodiment (and a composition containing it) has properties which make it suitable for plastic and reconstructive surgery applications. Thus, the co-polyester and the composition are injectable, absorbable liquid polymer formulations (at ambient conditions and/or at human body temperature). The co-polyesters are long-absorbable fillers, i.e., they hydrolyze substantially completely in vivo, in an animal, such as a human, not later than about 700 days, such as not later than about 560 days, e.g., within about 15 to about 18 months, or within about 300 to about 700 days from the time of administration of the co-polyesters into the tissue.
Two types of co-polyesters are included in this embodiment: A) high molecular weight (MW) co-polyesters; and B) low MW co-polyesters.
A. High MW Co-Polyesters
The high MW co-polyesters have Tg (glass transition temperature) of about -30 to about -60.degree. C., such as about -35 to about -55.degree. C., or about -38.5 to about -55.degree. C., and they include about 50 to about 80%, such as about 50 to about 70% by weight, of the epsilon-caprolactone component, based on the total weight of the co-polyester. The co-polyester has melt viscosity of about 10,000 to about 120,000, such as about 11,000 to about 100,000, or about 11,500 to about 60,000 cps (centipoise). The co-polyester comprises from about 20 to about 50% by weight of the polycondensation polyester based on the total weight of the co-polyester. The polycondensation polyester has Tg of about 5 to about -20.degree. C., such as about 0 to about -15.degree. C.
The co-polyester includes the reaction product of a polycondensation polyester and epsilon-caprolactone, added in the second, ring-opening polymerization ("ROP") stage. The polycondensation polyester comprises the reaction product of diglycolic acid and/or a derivative thereof and a diol. The derivative of the diglycolic acid may be 3,6-dioxaoctanedioic acid, 3,6,9-trioxaundecanedioic acid, and combinations thereof. Suitable diols include, without limitations, ethylene glycol, diethylene glycol (DEG), and N-methyldiethanolamine (NMDEA).
The co-polyester of this embodiment is prepared as discussed below.
The polycondensation polyester may be synthesized by conventional techniques using conventional processes. For example, in a condensation polymerization, diglycolic acid and ethylene glycol may be polymerized in the presence of a catalyst at elevated temperatures and reduced pressures. A variety of catalysts may be used, but organometallic compounds have been found to be useful.
The catalyst for the polycondensation step of the synthesis is preferably tin based, e.g., stannous octoate. The most desirable catalyst is dibutyltin oxide which is present in the diglycolic acid/ethylene glycol monomer mixture at a sufficiently effective molar ratio of monomer to catalyst, e.g., ranging from about 5,000/1 to about 100,000/1. For example, the ratio of 10,000/1 has been found to be quite suitable. The reaction is typically carried out at a temperature range from about 100.degree. C. to about 220.degree. C., preferably from about 140.degree. C. to about 180.degree. C., under an inert atmosphere until esterification of diglycolic acid is complete. Preferably, 165.degree. C. has been found to be a desirable reaction temperature when employing a vertically stirred reactor. It should be noted that the optimum reaction temperature may be reactor and catalyst level dependent but can be found by one having ordinary skill in the art through routine experiments. The first stage of the polycondensation reaction (inert gas at atmospheric pressure) is followed by polymerization under reduced pressure until the desired molecular weight and viscosity are achieved. Instead of ethylene glycol, other diols may be used, such as, diethylene glycol (DEG), or N-methyldiethanolamine (NMDEA). When other diols are used, synthesis of the polycondensation polyester may be conducted in a similar manner, as will be apparent to skilled persons.
The weight average molecular weight of the polycondensation polymer (i.e., polycondensation polyester) can range from about 5,000 to about 30,000 g/mol, from about 7,000 to about 20,000 g/mol, or can be about 10,000 g/mol. This corresponds to an inherent viscosity (IV) range from about 0.25 to about 0.60 dL/g.
The amount of polycondensation polyester used to prepare the co-polyester is about 20 to about 50% by weight, based on the total weight of the co-polyester.
The co-polyester of this embodiment may be conveniently synthesized by the reaction of a dihydroxy poly (alkylene diglycolate) or a dihydroxy poly (diol diglycolate) homopolymer with the epsilon-caprolactone by conventional techniques using conventional processes. For example, the polycondensation polyester, made with a diol, is used as an .alpha.,.omega.-dihydroxy macroinitiator in a subsequent ring opening polymerization (ROP) with the epsilon-caprolactone. The epsilon-caprolactone monomer is copolymerized into the polycondensation polyester in the presence of a conventional organometallic catalyst at elevated temperatures. The catalyst for the ROP may be already present as residual catalyst in the polycondensation polyester or an additional catalyst may be added in this second step of the synthesis. A suitable catalyst added at the time of the ROP can be an organometallic catalyst. The ring-opening organometallic catalyst is preferably tin based, e.g., stannous octoate, and is present in a sufficiently effective amount in the monomer mixture, preferably at a molar ratio of the epsilon-caprolactone monomer-to-catalyst ranging from about 20,000/1 to infinity (i.e., no additional catalyst used). Thus one might utilize a tin-IV compound such as dibutyltin oxide at a diacid, for instance, diglycolic acid-to-catalyst ratio of about 10,000/1 to prepare the polycondensation polyester and then add a tin-II compound such as stannous octoate at an epsilon-caprolactone-to-added-catalyst molar ratio of about 240,000/1 at the time of the ring opening polymerization. The co-polyesters of the present invention may be synthesized alternately with no additional catalyst being added at the time of the ROP as described in Example 10A. While this example describes the co-polyesters of a different embodiment, persons of ordinary skill will readily understand how to adapt principles thereof to this embodiment of the invention.
The ROP step can be immediately conducted in the same reactor as that used to synthesize the polycondensation polyester immediately after the completion of the polycondensation step, if the reactor can provide adequate heat transfer and agitation. The epsilon-caprolactone can be added as a liquid. Alternately, the ROP can be conducted in a separate reactor at a later date, or in the reactor used for the polycondensation polyester at a later date. If this is the case, the polycondensation polyester is discharged from its reactor and is stored in an environment that minimizes water pick up and hydrolysis. The epsilon-caprolactone is then added. The reactor is closed and the pressure reduced. The reactor is usually held under vacuum for a prolonged period of time, for instance overnight, to allow drying. Nitrogen is then introduced into the reactor to bring the pressure to slightly greater than one atmosphere, and the purge cycle repeated for a total of three times. The temperature of the reaction mass is brought up to 130.degree. C. Once at this temperature, the agitator is activated. The temperature is then increased to 150.degree. C. to complete the mixing. This mixing step is essential to produce the co-polyesters of the present invention as inadequate mixing tends to allow the formation of homopolymeric sequences which can then crystallize to an extent greater than optimum. To ensure that reactants are fully mixed, in-situ spectroscopic probes (such as Near-Infrared) can be conveniently used. If additional catalyst is to be added, it is typically added once the batch has been completely mixed. The temperature is quickly brought up to the final reaction temperature, with 190.degree. C. in one embodiment, and held there for typically 18-20 hours. The exact reaction conditions will depend on the catalyst and its level; final reaction temperatures can vary from about 180.degree. C. to about 210.degree. C. and more preferably from about 190.degree. C. to about 200.degree. C. Reaction times can vary from about 2 hours to about 20 hours, depending on the catalyst and its level, and typically the reaction is conducted until the desired conversion of monomer to polymer is achieved.
Under the above described conditions, the co-polyesters of polycondensation polyester and epsilon-caprolactone will typically have a weight average molecular weight (MW) of about 10,000 to about 30,000, such as about 12,000 to about 26,000, or about 15,000 to about 25,000 g/mol (a.k.a. Daltons). These molecular weights correspond to inherent viscosity, typically between about 0.25 to about 0.90 deciliters per gram (dL/g), such as about 0.50 to about 0.80 dL/g, about 0.60 to about 0.70 dL/g, or about 0.65 dL/g, as measured in a 0.1 g/dL solution of hexafluoroisopropanol (HFIP) at 25.degree. C.
The co-polyester may be used in the plastic or reconstructive surgery as is, or in a composition (also referred to herein as a "formulation"), which includes the co-polyester and a biocompatible solvent. Suitable biocompatible solvents include, without limitations benzyl benzoate, tetraglycol, triacetin, Tween 20 (Polysorbate 20), Poly(ethylene glycol) sorbitan ether monolaurate and Tween80 (Polysorbate 80), Poly(ethylene glycol) sorbitan ether monooleate. The amount of the solvent in the formulation is such that it decreases pain associated with polymer injections. For example, the formulation may contain about 5% to about 60%, such as about 10% to about 50%, about 20% to about 40% by volume of the biocompatible solvent. The formulation may have melt viscosity of about 50 to about 20,000, such as about 100 to about 10,000, or about 1,000 to about 5,000 cps.
B. Low MW Co-Polyesters
As discussed above, in another aspect of this embodiment, the co-polyester has lower weight average molecular weight, and lower IV. These low viscosity, low MW materials allow injections through small needle size without using an organic solvent, or if the solvent is necessary, using it in relatively small concentrations. The weight average molecular weight of such co-polyester is about 3,000 to about 10,000, such as about 4,000 to about 6,000, or about 5,000 g/mol, and its IV is about 0.10 to about 0.35, such as about 0.2 to about 0.3, or about 0.25 dL/g. T.sub.g of this co-polyester is about -50.degree. C. to about -60.degree. C., such as about -55.degree. C. This co-polyester includes about 60 to about 80% by weight of the epsilon-caprolactone, and about 20 to about 40% by weight of the polycondensation polyester, based on the total weight of the co-polyester. This co-polyester has melt viscosity of about 5,000 to about 50,000, such as about 10,000 to about 40,000, or about 20,000 to about 25,000 cps (centipoise).
Such co-polyester is prepared by a slightly modified process. In particular, syntheses of such co-polyesters are accomplished by initially synthesizing a low molecular weight PEDG by reacting diglycolic acid with ethylene glycol, or low molecular weight PEEDG by reacting diglycolic acid with diethylene glycol. Then, to the PEDG or PEEDG (each of which may be referred to as a poly condensation polymer) is added an extra alcohol, such as diols (e.g., DEG, NMDEA) or a multi-hydroxyl alcohol (Quadrol, N,N,N',N'-tetra(2-hydroxypropyl)ethylene diamine), in the second copolymerization step conducted with epsilon-caprolactone, as illustrated in Examples 3A, 3B, 7A-7E. The weight average molecular weight of the PEDG or PEEDG can range from about 1,000 to about 2,000 g/mol. The PEDG or PEEDG (i.e., polycondensation polyester) has Tg of about -50 to about -60.degree. C., such as about -55.degree. C. Otherwise, synthesis of such low MW co-polyesters is carried out in substantially the same manner as that of the high MW co-polyesters, described above.
For all types and embodiments of co-polyesters used for plastic and reconstructive surgery, when the molecular weight of the polycondensation polymer is lower than about 1,000 g/mol, the molecular weight of the final co-polyester is too low to achieve the desired properties necessary for the plastic and reconstructive surgery applications of the co-polyester. Although molecular weight can be increased with increasing reaction time, it becomes increasingly difficult to achieve very high molecular weight. We have found, in general, that a molecular weight of the polycondensation polymer greater than about 30,000 g/mol, is not necessary to achieve desirable properties. One could however envision that this value is not an absolute bar. One might for instance, increase the molecular weight of the polycondensation polymer, and lower the amount of the epsilone-copralactone component used in the preparation of the final co-polyester.
Prior to the use of any of the co-polyesters of this embodiment for filling soft tissue (discussed below), the co-polyesters can be sterilized by conventional techniques, e.g., by gamma (.gamma.)-irradiation (20 Kgy). An interesting and important property of the co-polyesters is the substantial absence therein of residual monomers, before or after sterilization. As will be appreciated by those skilled in the art, this is a very desirable property, since some heretofore known polymers used for similar applications have been known to cause adverse tissue reactions attributed to the presence of monomers in the polymers.
A further aspect of the invention relates to a method of filling soft tissue, e.g., in a human, comprising administering any of the co-polyesters of this embodiment, either by themselves or in the composition which includes the co-polyester(s) and a biocompatible solvent. The method may be used for plastic or reconstructive surgery applications of soft tissue, such as the face of a patient, e.g., for lip augmentation, lip reconstruction or body contouring.
The method typically comprises administering the co-polyester, or the composition including the co-polyester, by injecting the co-polyester or the composition, into the subcutaneous layer of the skin in the embodiments wherein the facial cosmetic or reconstructive surgery is desired. In the embodiment wherein the co-polyester or composition is intended for lip augmentation or lip reconstruction, the injecting is above the muscle tissue of the lip. Depending on the afflicted area, the amount of the co-polyester or the composition used may vary, as will be apparent to those skilled in the art.
The method may comprise one or more than one injection to cover the desired area or to achieve the desired result.
All examples in this application are presented for illustrative purposes only, and they do not limit the scope of the disclosure, which is defined by the entire specification and claims.
Synthesis of Hydroxy Terminated Polyethylene Diglycolate) (PEDG)
A twin-agitated reactor with intermeshing HELICONE patterned blades (Atlantic 10CV reactor) was employed. After charging the reactor with 10.0 kg of diglycolic acid, 13.9 kg of ethylene glycol (EG) and 1.86 grams of dibutyltin oxide catalyst, the pressure was reduced to below 1 Torr and the vacuum preserved over night. The next day vacuum was released with dry nitrogen (argon can be substituted) and the heating of mixture started. When the reactor temperature reached 150.degree. C., an agitator speed was set to 30 RPM. Soon first distillate appeared containing mostly water, an esterification by-product. The reaction was continued at 165.degree. C. for a couple of more hours until approximately all water was distilled and/or first traces of EG appeared in the distillate. After the first nitrogen/argon stage was completed, pressure was lowered gradually to full vacuum in steps while the temperature of the batch was maintained at 165.degree. C. A vacuum of about 30-50 mTorr was maintained throughout the rest of the reaction. Melt and solution viscosities were regularly checked to ensure a polymer of a desired molecular weight. A hydroxy end-capped polymer was discharged after 75 hours of reaction time under vacuum. It was a fully amorphous, colorless viscous liquid with a glass transition temperature of about 3.degree. C. Weight average molecular weight was 12,000 g/mol; the resin exhibited an inherent viscosity (IV) of 0.35 dL/g as determined in HFIP at 25.degree. C. at a concentration of 0.1 g/dL.
Example 2 includes general description of the copolymerization step; specific examples of the individual samples follow in Examples 2A, 2B and 2C.
Co-Polymerization of Hydroxy Terminated Poly(Ethylene Diglycolate) with a Lactone Monomer, Epsilon-Caprolactone
A portion of the Polyethylene diglycolate made in Example 1 was added into an oven dried 250 milliliter round bottom flask. In the nitrogen glove box, the e-caprolactone and catalyst were charged. A mechanical stirrer, nitrogen adapter and stirrer bearing were added to the 250 ml flask's neck opening. The vessel was pulled under a vacuum of less than 500 mTorr at room temperature and held overnight. The polymer was reacted using a stepped temperature profile. The next day the flask was released to nitrogen and placed in the oil bath. The bath temperature was set to 120.degree. C. without agitation. Once the temperature reached approximately 95.degree. C. the mechanical stirrer was set at 4 RPM. When the temperature reached 120.degree. C., the oil bath setpoint was increased to 160.degree. C. and the mixing was increased to 6 RPM. When the melt appeared homogenous and clear, the agitation was reduced to 1/2 RPM and the temperature was raised to 190.degree. C. for 19 hours.+-.1 hour. After 19 hours.+-.1 hour the reaction was stopped and allowed to cool overnight under nitrogen.
All the glass inserts were removed from the flask, leaving only the mechanical stirrer, polymer resin and the round bottom flask. The flask was then wrapped in aluminum foil and the polymer product was removed from the reaction flask through liquid nitrogen quenching. The remaining glass shards were ground/sanded off of the polymer product. The polymer fragments were collected and placed in a Teflon coated pan. The pan was placed in the vacuum oven and pulled under vacuum overnight. The next day the vacuum oven was set to 110.degree. C. and the polymer was devolitized for 16 hours.
The Copolymerization of Hydroxy Terminated Poly(Ethylene Diglycolate) with a Epsilon-Caprolactone; PEDG/Cap 50/50 wt. %
A portion of the Poly(ethylene diglycolate) made in Example 1 (50 g) that was discharged after 28 hours (IV=0.25 dL/g) was placed into an oven dried 250 milliliter round bottom flask. In the nitrogen glove box, the e-caprolactone (50 g) and catalyst, stannous octoate (0.022 mL) were charged. A mechanical stirrer, nitrogen adapter and stirrer bearing were added to the 250 ml flask's neck opening. The vessel was pulled under a vacuum of less than 200 mTorr at room temperature and held overnight. The next day the flask was released to nitrogen and placed in the oil bath. The bath temperature was set to 120.degree. C. without agitation. Once the temperature reached approximately 95.degree. C. the mechanical stirrer was set at 4 RPM. When the temperature reached 120.degree. C., the oil bath setpoint was increased to 160.degree. C. and the mixing was increased to 6 RPM. When the melt appeared homogenous and clear, the agitation was reduced to 0.5 RPM and the temperature was raised to 190.degree. C. for 18 hours. After 18 hours the reaction was stopped and allowed to cool overnight under nitrogen.
All the glass inserts were removed from the flask, leaving only the mechanical stirrer, polymer resin and the round bottom flask. The flask was then wrapped in aluminum foil and the polymer product was removed from the reaction flask through liquid nitrogen quenching. The remaining glass shards were ground/sanded off of the polymer product. The polymer fragments were collected and placed in a Teflon coated pan. The pan was placed in the vacuum oven and pulled under vacuum overnight. The next day the vacuum oven was set to 110.degree. C. and the polymer was devolitized for 16 hours to remove any residual monomer. The discharged material was slightly yellowish, free flowing material at ambient condition with the weight average molecular weight of 15,000 g/mol, and the inherent viscosity of 0.48 dL/g.
The Copolymerization of Hydroxy Terminated Poly(Ethylene Diglycolate) with a Epsilon-Caprolactone; PEDG/Cap 40/60 wt. %
A portion of the poly(ethylene diglycolate) made in Example 1 (40 g) was added into an oven dried 250 milliliter round bottom flask. In the nitrogen glove box, the e-caprolactone (60 g) and catalyst, stannous octoate (0.027 mL) were charged. A mechanical stirrer, nitrogen adapter and stirrer bearing were added to the 250 ml flask's neck opening. The vessel was pulled under a vacuum of less than 200 mTorr at room temperature and held overnight. The next day the flask was released to nitrogen and placed in the oil bath. The bath temperature was set to 120.degree. C. without agitation. Once the temperature reached approximately 95.degree. C. the mechanical stirrer was set at 4 RPM. When the temperature reached 120.degree. C., the oil bath setpoint was increased to 160.degree. C. and the mixing was increased to 6 RPM. When the melt appeared homogenous and clear, the agitation was reduced to 0.5 RPM and the temperature was raised to 190.degree. C. for 19 hours. After 19 hours the reaction was stopped and allowed to cool overnight under nitrogen.
All the glass inserts were removed from the flask, leaving only the mechanical stirrer, polymer resin and the round bottom flask. The flask was then wrapped in aluminum foil and the polymer product was removed from the reaction flask through liquid nitrogen quenching. The remaining glass shards were ground/sanded off of the polymer product. The polymer fragments were collected and placed in a Teflon coated pan. The pan was placed in the vacuum oven and pulled under vacuum overnight. The next day the vacuum oven was set to 110.degree. C. and the polymer was devolitized for 16 hours to remove any residual monomer. The discharged material was slightly yellowish, free flowing material at ambient condition with the weight average molecular weight of 22,000 g/mol, and the inherent viscosity of 0.70 dL/g.
The Copolymerization of Hydroxy Terminated Poly(Ethylene Diglycolate) with a Epsilon-Caprolactone; PEDG/Cap 30/70 wt. %
A portion of the Poly(ethylene diglycolate) made in Example 1 (30 g) was added into an oven dried 250 milliliter round bottom flask. In the nitrogen glove box, the e-caprolactone (70 g) and catalyst, stannous octoate (0.031 mL) were charged. A mechanical stirrer, nitrogen adapter and stirrer bearing were added to the 250 ml flask's neck opening. The vessel was pulled under a vacuum of less than 300 mTorr at room temperature and held overnight. The next day the flask was released to nitrogen and placed in the oil bath. The bath temperature was set to 120.degree. C. without agitation. Once the temperature reached approximately 95.degree. C. the mechanical stirrer was set at 4 RPM. When the temperature reached 120.degree. C., the oil bath setpoint was increased to 160.degree. C. and the mixing was increased to 6 RPM. When the melt appeared homogenous and clear, the agitation was reduced to 0.5 RPM and the temperature was raised to 190.degree. C. for 20 hours. After 20 hours the reaction was stopped and allowed to cool overnight under nitrogen.
All the glass inserts were removed from the flask, leaving only the mechanical stirrer, polymer resin and the round bottom flask. The flask was then wrapped in aluminum foil and the polymer product was removed from the reaction flask through liquid nitrogen quenching. The remaining glass shards were ground/sanded off of the polymer product. The polymer fragments were collected and placed in a Teflon coated pan. The pan was placed in the vacuum oven and pulled under vacuum overnight. The next day the vacuum oven was set to 110.degree. C. and the polymer was devolitized for 16 hours to remove any residual monomer. The discharged material was slightly yellowish, waxy material at ambient condition with the weight average molecular weight of 24,000 g/mol, and the inherent viscosity of 0.72 dL/g.
EXAMPLES 3A and 3B
In Examples 3A and 3B, the same types of copolymers were prepared as in the above Examples, except that in the polycondensation step (similar to Example 1) a different diol was used: diethylene glycol (DEG), instead of ethylene glycol in Example 3B.
We found that physical properties of the copolymers containing DEG instead of ethylene glycol in the structure were not altered significantly. With the DEG-containing material we observed a slight increase in viscosity.
Synthesis of Hydroxy Terminated Poly(Ethoxyethylene Diglycolate) (PEEDG)
A dual-agitated reactor with intermeshing HELICONE patterned blades (D.I.T. 10CV reactor) was employed. After charging the reactor with 7.0 kg of diglycolic acid, 16.6 kg of diethylene glycol (DEG) and 1.3 grams of dibutyltin oxide catalyst, the pressure was reduced to below 1 Torr and the vacuum preserved over night. The next day vacuum was released by introducing dry nitrogen (argon can be substituted) and heating of the mixture was started, and the agitator was stared and set to 15 RPM in reverse. When the reactor temperature reached 150.degree. C., the agitator speed was reset to 20 RPM in forward direction. Soon first distillate appeared containing mostly water, an esterification by-product. The reaction was continued at 170.degree. C. for about 2 hours until approximately all water was distilled and/or first traces of EG appeared in the distillate. After the first nitrogen/argon stage was completed, pressure was lowered gradually to full vacuum while the temperature of the batch was maintained at 170.degree. C. A vacuum of about 30-50 mTorr was maintained throughout the rest of the reaction, a total time of approximately 80 hours. Melt and solution viscosities were regularly checked to ensure polycondensation polyester of a desired molecular weight. Hydroxy end-capped polycondensation polyester was discharged after different reaction time under vacuum. The discharged sample was a fully amorphous, colorless viscous liquid with a glass transition temperature of about -15.0.degree. C.
Synthesis of Lower Molecular Weight Copolyesters for Solventless Injections: PEEDG/Cap 30/70 with Diethylene Glycol, DEG
The description continues in the full USPTO document.
About 5,880 words. The USPTO PDF has it with every drawing.
Fees are due 3.5, 7.5 and 11.5 years after grant. This patent expired on November 5, 2025, so the fee marked "not paid" was the one that went unpaid.
ABSORBABLE POLYMER FORMULATIONS
Filed Sep 2007 · published Oct 2008Absorbable polymer formulations
Filed Sep 2007 · granted May 2013ABSORBABLE POLYMER FORMULATIONS
Filed Nov 2012 · published Apr 2013Absorbable polymer formulations
Filed Nov 2012 · granted Nov 2013Earlier publications, parents and continuations. None of them can still be enforced, or this patent would not be listed.
Prior art cited by the examiner or applicant. Useful when you check your own idea for novelty.
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